Evidence for the contribution of the X chromosome to Systemic Sclerosis susceptibility : association with the functional IRAK1 196Phe/532Ser haplotype

BACKGROUND: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. Until now, nothing is known about whether genes on the sex chromosomes can influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). OBJECTIVE.: To test for association with SSc the IRAK1 SLE-risk haplotype METHODS.: We tested for association the IRAK1 SLE-risk haplotype in a discovery set of 849 SSc and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which includes individuals from Italy (493 SSc, 509 controls) and Germany (466 SSc, 1083 controls), all individuals being of European Caucasian origin and of female gender. RESULTS.: Association between the IRAK1 haplotype and SSc was detected in the discovery set. In both discovery and replication sets the rs1059702 TT genotype was found to be associated with specific SSc subsets highlighting a potential contribution in disease severity. A meta-analysis provided evidence for an association between both T allele and TT genotype and the overall disease: OR 1.20 95%CI[1.06-1.35], P=0.003 and OR 1.49 95%CI[1.06-2.10], P=0.023, respectively. However, the most remarkable associations were observed with diffuse cutaneous, anti-topoisomerase I antibodies positive and SSc-related fibrosing alveolitis subsets: OR 2.35 95%CI[1.51-3.66], P=1.56×10(-4) , OR 2.84 95%CI[1.87-4.32], P=1.07×10(-6) and OR 2.09 95%CI[1.35-3.24], P=9.05×10(-4) , respectively. CONCLUSIONS.: Our study provides the first evidence for an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.